Two main groups of drugs used in the treatment of malignant disease are alkalyting agents and the antimetabolites. Ifosfamide is one of the widely used antineoplastic drug belonging to the alkalyting agents group.
Ifosfamide is chemically 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and is represented by the formula:
Ifosfamide is a white crystalline hygroscopic powder having a low melting point of 40° C. The powder has a water solubility of about 100 mg/ml.
Ifosfamide is used in the treatment of a variety of solid tumours including those of the cervix, endometrium, lung, ovary, testes and thymus as well as in sarcoma and in the treatment of Burkitts lymphoma. However, the treatment with Ifosfamide is associated with serious side effects such as haemorrhagic cystitis, myelosuppression, cardiac arrythmias, CNS disturbances, nephrotoxicity, haematological and gastro-intestinal reactions. The LD50 in mouse on intravenous administration has been reported to be 338 mg/kg body weight. Combination with the uroprotective agent, mesna, reduces the incidence of hamorrhagic cystitis. Thus, mesna is normally administered intravenously at a dose of 20% of the Ifosfamide dose at time zero (the time of administration of Ifosfamide), and then at 4 and 8 hours.
Typically, Ifosfamide is given intravenously either by injection or by infusion as a diluted solution containing less than 4% w/v of Ifosfamide. Ifosfamide is very susceptible to hydrolytic degradation and accordingly prompt administration of such solutions is generally required. Therefore, commercially it is predominately available in dry form and is supplied as sterile packaged dry powder for dissolution in water for injection prior to administration. However, the low melting point and the hygroscopic nature of Ifosfamide make it necessary to fill the powder with great care accurately controlling both temperature and humidity to achieve a sterile product. Further, prolonged storage of the dry powder also results in sintering and yellowing, which in turn leads to a reduction in dissolution rate thereby increasing the time necessary for reconstitution.
To overcome difficulties associated with the thermal and hydrolytic susceptibility, lyophilization of the drug has been attempted. However, the lyophilization process is quite time consuming and requires specialized equipment. Personnel exposure to the strongly cytotoxic Ifosfamide occurring during reconstitution of lyophilized powder is also very undesirable.
Hence, others have attempted to obtain a clear liquid Ifosfamide compositions, suitable for parenteral administration, that are stable over a period of time
U.S. Pat. No. 4,952,575 discloses preparation of an ethanolic solution of Ifosfamide containing 96% to 100% ethanol. Even though the degradation of Ifosfamide has been shown to be minimal, use of solvents in such a high concentration leads to other problems such as volatility, handling during manufacturing, and miscibility with blood on administration. As such, alcohol is pharmacologically active, which may also effect the person on administration of alcoholic solution of Ifosfamide.
U.S. Pat. No. 4,879,286 discloses a Cyclophosphamide formulated in a ready-to-dilute solution. The solution has organic polyols, namely propylene glycol and polyethylene glycol and their mixtures, as a solvent and also 0 to 50% water. The water may be partly replaced by 10 to 30% of ethanol.
WO 02/02125 discloses a liquid pharmaceutical composition for parenteral administration comprising Ifosfamide, solvent and optionally, conventional pharmaceutical carriers and excipients. According to the application, the solvent comprises 35–75% lower alcohol and 25–65% polyol. While lower alcohol solvent is usually ethanol, the polyol solvent is propylene glycol, glycerol and/or polyethylene glycol.
In both the U.S. Pat. No. 4,879,286 and WO 02/02125, the parenteral administration of larger amounts of polyols and alcohols lead to other problems like pain or irritation on injection, hemolysis, ototoxicity, cardiovascular effects, CNS effects and seizures. It may also lead to hyperosmolarity and lactic acidosis in patients with renal impairment.
WO 99/18973 describes a stable, ready-to-use liquor of Ifosfamide using Sodium chloride as a stabilizing agent. The invention also describes 10–500 mg/ml Ifosfamide composition containing Urea, sodium chloride and sodium dihydrogen phosphate. The compositions of the invention are said to be stable but there is no mention about the safety and toxicity of the composition. The higher concentration of urea in the formulation may lead to complications like hemolysis, irritation, phlebitis & thrombosis at the site of injection, and elevated blood ammonia & urea concentrations in patients with hepatic and renal function impairment.
WO 03/051297A2 describes a ready-to-use aqueous composition of Ifosfamide comprising 40–400 mM (10–100 mg/ml) of Ifosfamide in a pharmaceutically acceptable buffer. The patent suggests the use of buffers preferably from the group of Na2HPO4 and NaH2PO4 and K2HPO4 and KH2PO4. There is no report on the toxicity of Ifosfamide compositions disclosed in this patent.
Thus, there remains a need for a stable, concentrated Ifosfamide solution to facilitate handling during administration. In addition, there remains a need for Ifosfamide pharmaceutical compositions that exhibit less toxicity than the currently available compositions. The present invention meets this need.